The main objective of the study was to calculate potential cost savings that could have been generated by maximum generic substitution of antidepressants within the private health care sector of South Africa from 2004 to 2006. Data on computerised medicine claims of patients receiving one or more antidepressants during three consecutive years (i.e. 2004, 2005 and 2006) were elicited from a South African pharmaceutical benefit management company. The total study population consisted of 292 071 items (N = 5 982 869) on 273 673 prescriptions (N = 5 213 765) at a total cost of R56 183 697.91 (N = R1 346 210 929.00). A quantitative, retrospective drug utilisation review was conducted, and data were analysed using the Statistical Analysis System® programme. Potential cost savings were computed for criteria-eligible substances in the study population. Generic medicine constituted 58.7% (N = 292 071) of all antidepressants claimed, at a total cost of 28.2% (N = R1 346 210 929.00) of all incurred costs. With total substitution of the average price of all criteria-eligible innovators, a potential saving of 9.3% (N = R56 183 697.91) of the actual antidepressant cost over the study period was calculated. In developing countries with limited health care resources, generic medicines can be cost-saving treatment alternatives.